Chronic Weight Management: New Medications
Two new medications have recently been approved to help patients lose weight: lorcaserin and phentermine and topiramate extended-release.
It is no secret that obesity has become a significant health concern in the United States, now affecting approximately 30% of the population.1 Obesity is associated with an increased risk of many medical conditions such as hypertension, hyperlipidemia, diabetes, stroke, and heart disease and is also responsible for increased health care costs.1,2 As of 2008, obesity was the second-leading cause of preventable death in the United States.2
The National Institutes of Health defines normal weight as a body mass index (BMI) of 18.5 to 24.9 kg/m2, overweight as a BMI of 25 to 29.9 kg/m2, obese as a BMI greater than or equal to 30 kg/m2, and extreme obesity as a BMI of greater than or equal to 40 kg/m2.3 Optimal management of obese patients includes a combination of behavioral interventions targeted at improving diet and increasing physical activity.1 According to the US Food and Drug Administration (FDA), pharmacologic treatment should be considered for patients with a BMI at or above 30 kg/m2 or 27 kg/m2 if a weight-related comorbidity is present.3
Despite these recommendations, orlistat was the only FDA-approved agent for long-term management of obesity prior to 2012. Phentermine and diethyl-propion are also available, but are only approved for short-term use.2,4 These medications were preceded by numerous agents, including sibutramine, dexfenfluramine, and fenfluramine, which were removed from the market due to significant safety concerns.2,4,5 Left with few options, safe and effective medications for the treatment of obesity have been in high demand. To guide the development of new agents, the FDA released the following criteria. In order for a new agent to be proved effective, at least 1 of the following must be met:
- “The difference in mean weight loss between the active-product and placebo-treated groups is at least 5% and the difference is statistically significant.”
- “The proportion of subjects who lose greater than or equal to 5% of baseline body weight in the active-product group is at least 35%, is approximately double the proportion in the placebo-treated group, and the difference between groups is statistically significant.6”
This article will assist pharmacists with evaluating pharmacotherapy options for chronic weight management by highlighting 2 new agents that were recently approved—lorcaserin (Belviq) and phentermine and topiramate extended-release (PHN/TPM, Qsymia).
Pharmacology and Dosing
Lorcaserin received FDA approval in June 2012 for chronic weight management in combination with a reduced-calorie diet and increased physical activity in adults with either a BMI greater than or equal to 30 kg/m2, or 27 kg/m
2 if at least 1 weight-related comorbidity is present.7 Lorcaserin is a selective 5-HT2C agonist that is believed to activate receptors in the hypothalamus, leading to decreased food intake and satiety.8 Its high specificity for the 5-HT2c receptor, instead of the 5-HT2B receptor, is thought to minimize the risk of cardiac valvulopathy that is associated with previous non-selective 5-HT2 agonists such as fenfluramine and dexfenfluramine.4 The recommended dosing for lorcaserin is 10 mg by mouth twice daily. Although specific dose adjustments are not recommended, lorcaserin should be used with caution in patients with moderate renal impairment and avoided in end-stage renal disease. No dosage reductions are recommended for patients with mild to moderate hepatic impairment and its use has not been evaluated in severe hepatic dysfunction.8
Three randomized, placebo-controlled trials were conducted to evaluate the efficacy of lorcaserin. A total of 4292 subjects were enrolled in the active-product arms, which included male and female adults with a BMI of at least 30 kg/m2 or 27 kg/m2 with a weight-related comorbidity. After 1 to 2 years of treatment, lorcaserin achieved significant weight loss in all patients as well as improvements in other parameters such as glycated hemoglobin (HbA1C) in patients with diabetes. Lorcaserin met the first FDA criterion because 37.5% to 47.5% of subjects achieved greater than or equal to 5% of baseline weight loss across all 3 trials. However, it failed to achieve the first of the 2 FDA criteria listed above (see Table 1 for more detailed results).2,7,9-11 Based on these results, the package insert recommends discontinuing lorcaserin if at least 5% of baseline weight loss is not achieved within the first 12 weeks of use.8
Safety and Clinical Use
The most common side effects associated with lorcaserin include hypoglycemia in patients with diabetes (29.3%), headache (16.8%), dizziness (8.5%), nausea (8.3%), fatigue (7.2%), constipation (5.8%), dry mouth (5.3%), and vomiting (3.8%).2,8 The use of lorcaserin is only contraindicated in patients who are pregnant; however, caution should be used in several patient populations, including, but not limited to, those with valvular heart disease, psychiatric disorders, and cognitive impairment. Lorcaserin is also associated with precautions related to a risk of priapism, heart rate decreases, hematological changes, and prolactin elevations. Concomitant use of other serotonin-modulating medications can increase the risk of serotonin syndrome or neuroleptic malignant syndrome.8 Although initial concerns for the risk of cardiac valvulopathy were alleviated by low rates in the active product and placebo groups in clinical trials, the FDA is requiring the completion of 6 post-marketing studies to evaluate long-term cardiac outcomes.7
Phentermine and Topiramate Extended-Release
Pharmacology and Dosing
A combination of phentermine and extended-release topiramate (PHM/ TPM) was approved by the FDA in July 2012 for chronic weight management. PHN/TPM is approved for use in the same adult population as lorcaserin and should also be utilized with lifestyle modifications.12 Phentermine, a sympathomimetic amine and anorectic agent originally approved for short-term treatment of obesity, likely promotes weight loss through the release of catecholamines leading to reductions in appetite.12-14
Topiramate, a monosaccharide derivative initially approved for the treatment of epilepsy and for the prevention of migraine headaches, has been associated with appetite suppression and satiety enhancement through an unknown mechanism of action.12,14,16 (An online table contains specific dosage and titration instructions for this agent.) Patients with moderate to severe renal impairment or moderate hepatic impairment should not receive doses greater than PHN/TPM 7.5 mg/46 mg daily. Its use has not been evaluated in patients with end-stage renal disease on dialysis or with severe hepatic impairment. Patients should be instructed to take PHN/TPM once daily in the morning with or without food.12
The efficacy of PHN/TPM for weight loss was studied in 3 randomized, placebo-controlled trials, which randomized a total of 2246 subjects in the active product arms.15,16 These trials included male and female adults with a baseline BMI of at least 27 kg/m2, with or without comorbidities. PHN/TPM demonstrated statistically significant weight reduction and improvement in cardiometabolic variables after 1-year and 2-year follow-up periods. PHN/TPM both of the FDA criteria that are used to assess the efficacy of weight-loss agents. Specifically, 62% to 79% of patients receiving PHN/TPM throughout all trials lost at least 5% of their baseline body weight. In addition, the difference between weight loss in the active product and placebo-treated groups was at least 5% for all patients receiving standard treatment doses (see Table 2 for more detailed results).14-16
Safety and Clinical Use
The most common adverse events associated with the use of PHN/TPM include paresthesia (17%), dry mouth (16.6%), constipation (15.1%), upper respiratory tract infection (13.5%), nasopharyngitis, (10%), and headache (9.8%).12,17 Use of PHN/TPM is contraindicated in patients with glaucoma, hyperthyroidism, known hypersensitivity to sympathomimetic amines, or monoamine oxidase inhibitor use within the past 14 days, and during pregnancy. The Risk Evaluation and Mitigation Strategy requires that PHN/TPM only be dispensed through pharmacies certified by the manufacturer. Females of child-bearing potential should have negative pregnancy tests prior to therapy with PHN/TPM and monthly throughout treatment. Additional warnings associated with its use include the potential for elevations in resting heart rate, emergence or worsening of depression, and impairment of cognitive function. PHN/TPM may have additive effects with CNS depressants, potentiate the potassium-wasting action of diuretics, and cause alterations in plasma concentrations of oral contraceptives.12 To further assess the long-term safety of this agent, 10 post-marketing studies are required.17,18
Table 3: Phentermine and Topiramate Extended-Release Dosage and Titration Instructions12,17
- Start patients on PHN/TPM 3.75 mg/23 mg once daily for 14 days, then increase to the recommended dose of PHN/TPM 7.5 mg/46 mg once daily
- Evaluate weight loss after 12 weeks of treatment with PHN/TPM 7.5 mg/46 mg. If weight loss is <3% of baseline weight, discontinue treatment or escalate dose to PHN/TPM 11.25 mg/69 mg once daily for 14 days
- After 14 days of treatment with PHN/TPM 11.25 mg/69 mg, increase to the recommended dose of PHN/TPM 15 mg/92 mg once daily
- Evaluate weight loss after 12 weeks of treatment with PHN/TPM 15 mg/69 mg. If weight loss is <5% of baseline weight, discontinue treatment
- Taper drug upon discontinuing by taking a dose every other day for at least a week before stopping treatment.
Prior to the approval of these 2 new agents, orlistat received FDA approval in 1999 for managing obesity and reducing the risk of regaining weight after prior weight loss when used in combination with a reduced-calorie diet.19 This agent is available as both a prescription (Xenical) and over-the-counter product (Alli). This triacylglycerol lipase inhibitor leads to weight loss by preventing the absorption of dietary fat; therefore, its efficacy requires the presence of dietary fat. The most common side effects include oily spotting, flatus with discharge, and fecal urgency.20 Orlistat is also associated with a potential for decreased absorption of many medications, which requires separation of administration of the interacting agents.21
Weight Loss Medications in the Pipeline
Several agents are undergoing active investigation for their potential role in chronic weight management. For example, a combination of bupropion extended-release and naltrexone (Contrave) has demonstrated statistically significant weight loss in several randomized controlled trials with an acceptable safety profile. In addition, liraglutide is a glucagon-like peptide-1 analogue currently approved for treating type 2 diabetes mellitus and has also shown clinically significant, dose-dependent weight loss in randomized controlled trials.22
Role of the Pharmacist
Pharmacists are frequently approached for recommendations regarding prescription, over-the-counter, and herbal weight-loss products. Hospital pharmacists are optimally positioned to educate patients and providers regarding the risks and benefits of the available options, identify significant drug interactions, and determine appropriate weight-loss medications for specific patients. Pharmacists can also ensure that treatment duration is limited if clinically meaningful weight loss does not occur within 12 weeks of using lorcaserin and PHN/TPM at appropriate doses.
The approval of lorcaserin and PHN/TPM provides much-needed therapy options alongside orlistat for chronic weight management in combination with continued lifestyle modifications. Clinical experience and ongoing post-marketing trials will be important for determining long-term safety and defining the role of each agent in therapy.
Dr. Sievers is a PGY2 Pharmacotherapy Specialty Resident at University of North Carolina (UNC) Hospitals and Clinics and clinical adjunct faculty member at the UNC Eshelman School of Pharmacy in Chapel Hill, North Carolina. Dr. Smith is a PGY1 Pharmacy Practice Resident at UNC Hospitals and Clinics and clinical adjunct faculty member at the UNC Eshelman School of Pharmacy in Chapel Hill, North Carolina. Dr. Hawes is a clinical pharmacist practitioner at the UNC Family Medicine Center and clinical assistant professor at the UNC School of Medicine Department of Family Medicine in Chapel Hill, North Carolina.
- Moyer VA. Screening for the Management of Obesity in Adults: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med. 2012;157:373-378.
- Hurren KM, Berlie HD. Lorcaserin: An investigational serotonin 2C agonist for weight loss. Am J Health-Syst Pharm. 2011;68:2029-2037.
- Colman E. Food and Drug Administration’s Obesity Drug Guidance document: a short history. Circulation. 2012;125:2156-2164.
- Bello NT, Campbell SC. Two anti-obesity hopefuls and their safety. Expert Opin Drug Saf. 2012;11:681-683.
- Derosa G, Maffioli P. Antiobesity drugs: a review about their effects and their safety. Expert Opin Drug Saf. 2012;11:459-471.
- Food and Drug Administration. Guidance for industry developing products for weight management. www.fda.gov/downloads/Drugs/.../Guidances/ucm071612.pdf. Updated February 2007.
- FDA approves Belviq to treat some overweight or obese adults [press release]. FDA website. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm309993.htm. Updated June 27, 2012.
- Belviq [package insert]. Woodcliff Lake, NJ: Eisai, Inc; 2012.
- Smith, SR, Weissman NJ, Anderson CM, et al. Multicenter, placebo-controlled trial of lorcaserin for weight management. N Engl J Med. 2010;363:245-256.
- O’Neil PM, Smith SR, Weissman NJ, et al. Randomized placebo-controlled clinical trial of lorcaserin for weight loss in type 2 diabetes mellitus: the BLOOM-DM study. Obesity. 2012;20:1426-1436.
- Fidler MC, Sanchez M, Raether B, et al. A one-year randomized trial of lorcaserin for weight loss in obese and overweight adults: the BLOSSOM trial. J Clin Endocrinol Metab. 2011;96:3067-3077.
- Qsymia [package insert]. Mountain View, CA: VIVUS, Inc; 2012.
- Colman E, Golden J, Roberts M. The FDA’s assessment of two drugs for chronic weight management. N Engl J Med. 2012;367:1577-1579.
- Garvey TM, Ryan DH, Look M, et al. Two-year sustained weight loss and metabolic benefits with controlled-release phentermine/topiramate in obese and overweight adults (SEQUEL): a randomized, placebo-controlled, phase 3 extension study. Am J Clin Nutr. 2012;95:297-308.
- Gadde KM, Allison DB, Ryan DH, et al. Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): a randomized, placebo-controlled, phase 3 trial. Lancet. 2011;377:1341-1352.
- Allison DB, Gadde KM, Garvey WT, et al. Controlled-release phentermine/topiramate in severely obese adults: a randomized controlled trial (EQUIP). Obesity. 2011;20:330-342.
- Steffen KJ, Kolotkin RL. A review of the combination of phentermine and topiramate extended-release for weight loss. Comb Prod Ther. 2012;2:1-17.
- Morrato EH, Allison DB. FDA approval of obesity drugs: a difference in risk- benefit perceptions. JAMA. 2012;308:1097-1098.
- Orlistat (marketed as Alli and Xenical) information [press release]. FDA website. www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm180076.htm. Updated May 26, 2010.
- Eckel RH. Nonsurgical management of obesity in adults. N Engl J Med. 2008;358:1941-1950.
- Drugs for weight loss. Pharmacist’s Letter website. http://pharmacistsletter.therapeuticresearch.com/pl/ArticleDD.aspx?nidchk=1&cs=&s=PL&pt=2&fpt=31&dd=261109&pb=PL&searchid=40056941&segment=2716. Updated October 2012.
- Jindal A, Brietzke S, Sowers JR. Obesity and the cardiorenal metabolic syndrome: therapeutic modalities and their efficacy in improving cardiovascular and renal risk factors. Cardiorenal Med. 2012;2:314-327.